Sustained/enhanced antipyretic response

ABSTRACT

Sustained and enhanced antipyretic response is elicited in a mammalian organism in need of such treatment, i.e., a mammal suffering from elevated body temperature (fever), by administering thereto a unit dosage sustainedly enhancing, antipyretically effective amount of the free acid S(+) flurbiprofen enantiomer, said enantiomer being substantially free of its R(-) flurbiprofen antipode.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part application of Ser. No.384,101, filed Jul. 21, 1989, now U.S. Pat. No. 4,927,854, which is acontinuation of Ser. No. 137,866, filed Dec. 24, 1987, now abandoned,both of which are hereby incorporated by reference.

CROSS-REFERENCE TO COMPANION APPLICATIONS

Our copending application, Ser. No. 356,850 was filed May 25, 1989, nowU.S. Pat. No. 4,980,375, and Ser. No. 398,482 was filed Aug. 25, 1989,now U.S. Pat. No. 4,962,124.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to the use of free acid S(+) flurbiprofento elicit a sustained and enhanced antipyretic response in mammalianorganisms in need of such treatment, and to certain pharmaceuticalcompositions comprising unit dosage effective amounts of S(+)flurbiprofen.

2. Description of the Art

Flurbiprofen, also known as(±)-2-fluoro-α-methyl-[1,1'-biphenyl]-4-acetic acid, as(±)-2-fluoro-α-methyl-4-biphenylacetic acid or as(±)-2-(2-fluoro-4-biphenylyl)propionic acid, is described in U.S. Pat.No. 3,755,427 and has the structural formula: ##STR1## The compound iswell-known as a nonsteroidal anti-inflammatory drug having analgesic andantipyretic activity. Flurbiprofen is marketed in the United States forthe treatment of arthritis but not as an analgesic and it has been onthe market in numerous countries overseas, including Europe, for anumber of years. Tradenames and codenames by which it is known includeAnsaid, Cebutid, Froben, BTS 18322 and U-27182. As Froben, the drug isavailable abroad as tablets containing 50 or 100 mg of flurbiprofen. Forrheumatic disorders such as rheumatoid arthritis, it is recommended at adaily dose of 150 to 200 mg in divided doses of two to four per day,increased to a daily dose of 300 mg in acute conditions. See Martindale,The Extra Pharmacopoeia, 28th edition, ed. James E. F. Reynolds, London,The Pharmaceutical Press, 1982, p. 255. As an analgesic, it is usuallyadministered at the 50 mg dosage level every 4 to 6 hours, up to 300 mgper day. Flurbiprofen has been found useful in controlling acute andchronic pain, including that associated with ankylosing spondylitis,osteoarthritis, rheumatoid arthritis, postsurgical dental pain,postsurgical gynecological pain, postpartum uterine pain, primarydysmenorrhea, cancer pain, the pain of acute gout and the pain of acutebursitis/tendinitis of the shoulder. See The American Journal ofMedicine, Proceedings of a Symposium, "Control of Acute and Chronic Painwith Ansaid (Flurbiprofen)", ed. Abraham Sunshine, M. D., Volume 80(3A), Mar. 24, 1986.

As is apparent from its chemical nomenclature, flurbiprofen is a racemicmixture. It is only the racemic mixture which has in fact ever beenmarketed. There have, however, been a few isolated studies of theindividual S(+) and R(-) isomers reported in the literature. Thesereflect that the S(+) enantiomer, analogously to other 2-arylpropionicacids, is the active form of flurbiprofen.

Hutt et al, J. Pharm. Pharmacol., 35, 693-704 (1983), reviewed theearlier work on the metabolic chiral inversion of 2-arylpropionic acids,including ibuprofen, which they indicated was the first substituted2-arylpropionic acid conclusively shown to undergo the inversion as wellas the most studied member of the group. The authors noted that earlyworkers found no significant difference in in vivo activity among theR(-) and S(+) isomers and the racemic mixture of ibuprofen in threedifferent animal models, but very large differences in vitro between theR(-) and S(+) isomers, ascribing this discrepancy to the virtuallyquantitative conversion of the R(-) to the active S(+) isomer in vivo.

In the same paper, Hutt et al reported that, in contrast, for severalother 2-arylpropionic acids, the inactive R(-) isomer was not convertedin vivo to the active S(+) isomer as readily as ibuprofen, although theconversion seemed to occur to some extent over time. Naproxen, theynoted, has been the only compound marketed as the S(+) enantiomer todate. Hutt et al concluded:

It is likely that benefits will be obtained from the use of theS(+)-enantiomer of 2-arylpropionates as drugs as opposed to theracemates. This is only found at present in the case of naproxen. Incases of rapid inversion, the inactive R(-) isomer serves merely as aprodrug for the active S(+)-antipode. Where inversion is slow, the R(-)enantiomer is an unnecessary impurity in the active S(+) form. Use ofthe S(+)-enantiomer would permit reduction of the dose given, removevariability in rate and extent of inversion as a source of variabilityin therapeutic response and would reduce any toxicity arising fromnon-stereospecific mechanisms.

Thus, in cases of rapid inversion, such as ibuprofen, wheresubstantially equivalent in vivo responses have been reported for theindividual enantiomers and the racemic drug, Hutt et al suggested thatno benefits would be obtained from the use of the S(+) isomer becausethe inactive R(-) isomer merely acts as a prodrug for the active S(+)form. Contrariwise, in cases where chiral inversion is slow, e.g.,naproxen, the use of the S(+) enantiomer is desirable for the severalreasons enumerated by Hutt et al. Indeed, naproxen has been reported tobe marketed as the d-isomer for one of the reasons given by Hutt et al,i.e., to reduce side effects (Allison et al, "Naproxen," Chapter 9 inAnti-inflammatory and Anti-Rheumatic Drugs, eds. Rainsford and Path, CRCPress Inc., Boca Raton, Fla., 1985, p. 172). However, the 1983 Hutt etal review is silent as to the possibility of chiral inversion in thecase of flurbiprofen.

Another general report on earlier work has been provided by Hutt et alin Clinical Pharmacokinetics, 9, 371-373 (1984). In this article on theimportance of stereochemical considerations in the clinicalpharmacokinetics of 2-aryl-propionic acids, the authors tabulatedrelative potencies of the enantiomers of a number of 2-arylpropionicacids in vivo and in vitro. The in vitro results showed the S or (+)isomer in each case to be the more active species. In vivo, however, theresults were not consistent across the entire class. Thus, the resultsfor naproxen demonstrated the S or (+) isomer to be much more active invivo, indicating a relatively slow inversion of the inactive R or (-)isomer to the active S or (+) isomer; the results for fenoprofen andibuprofen, on the other hand, demonstrated the inactive R or (-) and theactive S or (+) isomers to be approximately equally effective in vivo,indicating a rapid inversion of R or (-) isomer to S or (+) isomer. Huttet al indicated that flurbiprofen had an S(+)/R(-) activity ratio invivo of 878 and in vitro 2-16; the in vitro study involved antagonism ofrat SRS-A on the tracheal chain of guinea pigs and the in vivo studyassessed guinea pig anaphylaxis. The reference cited by Hutt et al forthe flurbiprofen studies was Greig et al, J. Med. Chem. 18, 112-116(1975).

Greig et al, who were associated with the Upjohn Company, one of thedevelopers of flurbiprofen, studied the antagonism of slow reactingsubstance in anaphylaxis (SRS-A) and other spasmogens on the guinea pigtracheal chain by hydrotropic acids. Greig et al also studied theability of the hydrotropic acids to protect guinea pigs againstanaphylaxis. Among the substances tested were racemic flurbiprofen, (+)flurbiprofen and (-) flurbiprofen.

In the in vitro testing, the (+) isomer was found to be many times moreeffective than the racemate; indeed, the authors found that the (-)isomer inhibited the effect of the (+) isomer in antagonism of rat SRS-Aon guinea pig trachea in vitro. In the in vivo testing, Greig et alfound that flurbiprofen and its isomers were active in protectingsensitized guinea pigs against anaphylactic shock when they werechallenged 4 weeks after sensitization. These results correlated wellwith the in vitro activity. In vivo, the (+) isomer had more than atwo-fold effect over the racemate; at 80% protection, the (+) isomer was5 to 7 times more active than the racemic mixture. The (-) isomer wasthe least active of the three compounds.

The Greig et al studies concerned themselves with anaphylaxis andbronchospasm; as such, they have no relevancy to an antipyreticresponse.

Nishizawa et al, also associated with Upjohn, reported in ThrombosisResearch 3, 577-588 (1973) on flurbiprofen as a potent inhibitor ofplatelet aggregation in animals and man. They found that the plateletanti-aggregating effect resided in the d-isomer; the 1-isomer waswithout anti-aggregating effect and neither counteracted nor enhancedthe effect of the d-isomer. The optical antipodes were tested in rats.Anti-aggregating effects, however, do not correlate with models foranalgesia or inflammation.

Kulmacz et al, J. Biol. Chem. 260, 12572-12578 (1985), studied theinteraction of flurbiprofen with prostaglandin H synthase. They reportedthat 1.2 ±0.1 mol of S(+) flurbiprofen per mol of synthase dimerresulted in maximum inhibition of the cyclooxygenase enzyme. Racemicflurbiprofen required 2.4±0.3 mol per mol synthase dimer for fulleffect, and the R(-) isomer was not inhibitory, even at a ratio of2.5/dimer. From their own studies and those of Nishizawa et al ininhibiting rat platelet aggregation, Kulmacz et al concluded that theflurbiprofen isomers follow the pattern observed for manyanti-inflammatory agents, i.e., the dextrorotatory form is usually morepotent pharmacologically than the levorotatory isomer. This is borne outby the teachings of Armitage et al, U.S. Pat. No. 4,501,727, dated Feb.26, 1985. The Armitage et al patent relates to a novel light-stableN-methyl-D-glucamine salt of the dextrorotatory or (+) isomer. Itteaches that flurbiprofen has anti-inflammatory, analgesic andantipyretic properties, and that the (+) enantiomer is thepharmacologically active isomer.

In summary, the current state of the art assumes that, in mammals,analogously to other 2-arylpropionic acid NSAID's, the S(+) form is theactive enantiomer of flurbiprofen. However, there do not appear to beany human or other animal experiments on efficacy of the separateenantiomers in antipyretic models reported in the literature. The priorart, moreover, is conspicuously silent in respect to any sustainedlyenhanced alleviation of mammalian fever utilizing whatever form of theflurbiprofen drug species.

SUMMARY OF THE INVENTION

Surprisingly, the present inventors now find that S(+) flurbiprofen freeacid can be advantageously administered to mammals suffering fromelevated body temperature, especially humans, to not only elicit a morepotent antipyretic response but also to evoke such enhanced responseover a longer period of time than possible by administration of the samedose of flurbiprofen in its racemic form.

In one aspect, the present invention thus provides a method of providingan enhanced and sustained or prolonged antipyretic response in a mammal,said method comprising administering to a mammal in need of suchtreatment an effective antipyretic enhancing and sustaining amount ofS(+) flurbiprofen free acid substantially free of R(-) flurbiprofen.

In yet another aspect, the present invention provides a pharmaceuticalcomposition of matter for use in eliciting an enhanced and sustainedantipyretic response in mammals, especially humans, said compositioncomprising an effective antipyretic enhancing and sustaining unit dosageamount of S(+) flurbiprofen free acid substantially free of R(-)flurbiprofen. Typically, S(+) flurbiprofen is associated with a nontoxicpharmaceutically acceptable inert carrier or diluent therefor.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

The term "flurbiprofen" or "racemic flurbiprofen" as used herein isintended to encompass not only(±)-2-fluoro-α-methyl-[1,1'-biphenyl]-4-acetic acid itself but also anypharmaceutically acceptable salt thereof.

The term "S(+) flurbiprofen" as used herein is intended to encompass notonly the preferred free acid dextrorotatory or S(+) isomer of2-fluoro-α-methyl-[1,1'-biphenyl]-4-acetic acid but also includes thepharmaceutically acceptable, antipyretically effective simple metalsalts thereof, e.g., Na, K and Ca. The expression "substantially free ofR(-) flurbiprofen" as used in conjunction with the term "S(+)flurbiprofen" means that the S(+) flurbiprofen is sufficiently free ofR(-) flurbiprofen [which is the levorotatory form or R(-) isomer of2-fluoro-α-methyl-[1,1'-biphenyl]-4-acetic acid or salt thereof] toexert the desired sustained and enhanced antipyretic effect. Practicallyspeaking, this means that the active ingredient should contain at least90% by weight S(+) flurbiprofen and 10% or less by weight R(-)flurbiprofen. Preferably, the weight ratio of S(+) flurbiprofen to R(-)flurbiprofen is greater than or equal to 20:1, more preferably greaterthan 97:3. Ideally the S(+) flurbiprofen is 98, 99 or more % by weightfree of R(-) flurbiprofen, i.e., the weight ratio of S to R isapproximately equal to or greater than 98:2 or 99:1.

Where specific amounts of S(+) flurbiprofen are set forth below, itshould be understood that, unless otherwise specified, the amounts aregiven in mg of the acid, not of a salt. Moreover, unless otherwisespecified, for simplicity's sake the amounts given represent totalflurbiprofen content, most of which is in the S(+) form. For example,"50 mg S(+) flurbiprofen" means 50 mg total flurbiprofen at least 90% ofwhich is in the S(+) form, preferably at least 95%.

S(+) flurbiprofen, in accord with the present invention, produces thefollowing unexpected results:

(1) the antipyretic effect of flurbiprofen on the mammal issignificantly better than by use of racemic flurbiprofen, at a doseone-half that of racemic flurbiprofen; and

(2) a greater antipyretic response is elicited particularly after thefirst hour than is elicited by twice as much racemic flurbiprofen.

These unexpected results can be achieved in the treatment of feverresponsive to an NSAID (non-steroidal anti-inflammatory drug). Thisincludes the fever associated with respiratory infections such as coldsand flu.

For patients suffering from such elevated body temperature, who requiretreatment at a particular dose of racemic flurbiprofen, the duration andextent of effective relief is clearly of paramount importance. Thepresent inventors' discovery that S(+) flurbiprofen, when used in placeof racemic flurbiprofen at one-half the dosage of the racemate,substantially enhances the antipyretic response, especially after thefirst hour, is therefore very significant. It is likewise quiteunexpected.

The precise amount of S(+) flurbiprofen for use in accord with thepresent invention will vary depending, for example, on the size and kindof the mammal and the condition for which the drug is administered. Foruse in humans, the antipyretic effective amount of S(+) flurbiprofenwill typically be from about 12.5 to 50 mg, although greater amounts(e.g., 75 mg) may be employed if needed for pain relief and if toleratedby the patient. The daily dose in humans preferably will not exceed 150mg S(+) flurbiprofen, although greater amounts could be employed iftolerated by the patient. Preferred unit dosage compositions for use inthe treatment of slight to moderate fever contain 12.5, 25 or 50 mg S(+)flurbiprofen.

While the compositions for use in the invention are preferably for oraluse, they may also be formulated for and administered by other routeswhich are known for administering antipyretic drugs, e.g., assuppositories or parenteral solutions, or as topical formulations suchas ointments, gels, creams, lotions, solutions, impregnated bandages orother topical delivery devices, and so forth. Also, it should be notedthat the preferred human dosage levels indicated above are for use inadults; pediatric compositions would contain proportionately less of theactive ingredient.

The compositions for use herein are very conveniently administered tomammals by any route of administration suitable for racemicflurbiprofen, e.g., oral, rectal, topical or parenteral. Preferably S(+)flurbiprofen is formulated with any suitable nontoxic pharmaceuticallyacceptable inert carrier material. Such carrier materials are well knownto those skilled in the art of pharmaceutical formulations. For thosenot skilled in the art, reference is made to the text entitledRemington's Pharmaceutical Sciences, 17th edition, 1985, ed. Alfonso R.Gennaro, Mack Publishing Company, Easton, Penna. 18042. In a typicalpreparation for oral administration, e.g., tablet, capsule or caplet,S(+) flurbiprofen in an effective antipyretic amount and substantiallyfree of R(-) flurbiprofen, is combined with any oral nontoxicpharmaceutically acceptable inert carrier such as lactose, starch(pharmaceutical grade), dicalcium phosphate, calcium sulfate, kaolin,mannitol and powdered sugar. Additionally, when required, suitablebinders, lubricants, disintegrating agents and coloring agents can alsobe included. Typical binders include starch, gelatin, sugars such assucrose, molasses and lactose, natural and synthetic gums such asacacia, sodium alginate, extract of Irish moss, carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone, polyethylene glycol,ethylcellulose and waxes. Typical lubricants for use in these dosageforms can include, without limitation, boric acid, sodium benzoate,sodium acetate, sodium chloride, leucine and polyethylene glycol.Suitable disintegrators can include, without limitation, starch,methylcellulose, agar, bentonite, cellulose, wood products, alginicacid, guar gum, citrus pulp, carboxymethylcellulose and sodium laurylsulfate. If desired, a conventional pharmaceutically acceptable dye canbe incorporated into the dosage unit form, i.e., any of the standardFD&C dyes. Sweetening and flavoring agents and preservatives can also beincluded, particularly when a liquid dosage form is formulated, e.g., anelixir, suspension or syrup. Also, when the dosage form is a capsule, itmay contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills or capsules may be coated with shellacand/or sugar. Such compositions should preferably contain at least 0.1%of S(+) flurbiprofen; generally, S(+) flurbiprofen will be from about 2%to about 60% of the weight of the unit. Typical unit dosage forms fororal administration will preferably contain about 12.5 to 50 mg S(+)flurbiprofen, if formulated for immediate release, as is preferred. Ifthe composition is intended for sustained release, much larger amountsof the active ingredient would of course be incorporated into anindividual unit; in such case, at least 12.5, and preferably up to 50 mgof the total amount of S(+) flurbiprofen, should be formulated forimmediate release so as to obtain the desired degree of enhanced andprolonged antipyretic response.

A typical capsule for oral administration may contain, in addition tothe selected amount of S(+) flurbiprofen, the following combination ofinactive ingredients/carrier materials: D&C Yellow 10, FD&C Blue 1, FD&CYellow 6, gelatin, lactose, magnesium stearate and titanium dioxide.

Moreover, the compositions for use in obtaining an enhanced andprolonged antipyretic response in accord with the present invention may,in addition to the selected dose of S(+) flurbiprofen, also containother active ingredients and/or enhancing agents. Thus, for example,S(+) flurbiprofen may be combined with such ingredients and agents ashave been described for combination with racemic flurbiprofen, e.g.,caffeine or other xanthine derivative, a narcotic analgesic (with orwithout caffeine), a skeletal muscle relaxant, an antihistamine,decongestant, cough suppressant and/or expectorant. See, for example,Sunshine et al, U.S. Pat. No. 4,486,436, issued Dec. 4, 1984; Sunshineet al, U.S. Pat. No. 4,552,899, issued Nov. 12, 1985; Sunshine et al,U.S. Pat. No. 4,567,183, issued Jan. 28, 1986; and Sunshine et al, U.S.Pat. No. 4,619,934, issued Oct. 28, 1986; and Sunshine et al, U.S. Pat.No. 4,722,938, issued Feb. 2, 1988.

To establish the efficacy of the compositions of this invention inhumans, patients with moderate to high fever requiring an oralantipyretic agent, can be administered S(+) flurbiprofen or racemicflurbiprofen. To determine antipyretic efficacy, the temperature of thepatients are taken at different intervals of time and the two treatmentgroups are compared. Appropriate statistical methods, including survivalanalysis, can be used to show that the S(+) enantiomer has a longerduration and analysis of various standard methods can be used to showthat S(+) is more efficacious; (Cox, D. R., "Regression Models and LifeTables," Journal Royal Statistical Society, Series B, Volume 34:187-202,1972).

S(+) flurbiprofen for use in the method and compositions of the presentinvention can be prepared by a variety of methods, such as by resolutionof racemic flurbiprofen.

Maitre et al, J. Chromatogr. 299, 397-403 (1984) have resolved racemicflurbiprofen and a number of other arylpropionic acids byhigh-performance liquid chromatographic (HPLC) separation. Thediastereoisomeric derivatives of the racemic acids with S(-)1-phenylethylamine were synthesized and then separated by the HPLCmethod. The pure amides could then be used to regenerate thecorresponding acids, now in optically pure form, as is well-known.

HPLC methods other than Maitre et al's for resolving enantiomers ofNSAID's such as ibuprofen, ketoprofen and fenoprofen, and likelyadaptable to resolution of flurbiprofen, include the method of Doyle etal, Pharm. Technol. 9(2), 28-32 (1985), which utilizes conversion of theracemate to its amide derivatives for effective resolution; that ofWainer et al, J. Chromatogr. 284(1), 117-124 (1984), which utilizesconversion of the drug to 1-naphthalenemethylamide derivatives; and thatof Sallustio et al, J. Chromatogr., 374, 329-337 (1986), which employsconversion of the drug to the R and S derivatives ofR-2-phenylethylamine.

A method for derivatizing flurbiprofen and other nonsteroidalanti-inflammatory drugs with optically active amphetamine(α-methylbenzeneethanamide) has been described by Singh et al, J.Chromatogr. Biomed. Appln. 378, 125-135 (1986). Those authors alsoprovide a summary of the usual methods for resolving enantiomers, i.e.,(1) by direct separation on chiral HPLC or GC (gas chromatographic)columns, or (2) by diastereoisomer formation, by reaction with anoptically pure resolving agent, followed by chromatographic separationon an optically inactive column. Singh et al's method is a new versionof the second approach, using optically active amphetamine as theresolving agent, followed by separation of the diastereoisomers bycapillary gas chromatography with nitrogen-phosphorus detection. (Theacid, now in optically pure form, could of course then be regeneratedfrom the salt as is well-known.) The usual method in the art utilizesoptically active α-methylbenzylamine and involves preparation of thediastereoisomeric NSAID-α-methylbenzylamide directly by means of acoupling agent (e.g., 1,1'-carbonyldiimidazole) or via the NSAID acidchloride (prepared with thionyl chloride). An example of the firstapproach has been provided by Hermansson et al, Journal of LiquidChromatography, 9 (2 and 3), 621-639 (1986); those authors describedirect liquid chromatographic resolution of such acidic drugs asibuprofen, ketoprofen, naproxen and 2-phenoxy-propionic acid, using achiral α₁ -acid glycoprotein column (Enantiopak®).

More generally speaking, the S(+) isomer can be separated from racemicflurbiprofen by preparing a salt of flurbiprofen with an alkaloid orsimilar resolving agent such as cinchonidine, then separating theproducts by fractional crystallization from a solvent in which thedextrorotatory isomer is least soluble. The d-salt can then be acidcleaved to yield S(+) flurbiprofen. Compare, for example, Alvarez, U.S.Pat. No. 3,637,767, issued Jan. 25, 1972, which relates to resolution ofnaproxen and related compounds; and Kaiser et al, J. Pharm. Sci. 65(2),269-273 (1976), which relates to resolution of ibuprofen.

While S(+) flurbiprofen may be conveniently obtained by resolution ofracemic flurbiprofen, it may also be possible to utilize a chemical ormicrobiological synthetic process which will provide the S(+) enantiomerdirectly. One such chemical process is provided by Schloemer, U.S. Pat.No. 4,542,237, which describes a process for preparing α-arylalkanoicacids utilizing novel α-hydroxy alkyl aryl ketals as intermediates. Astaught in column 9 of the Schloemer patent, the process is advantageousin that the α-hydroxy ketal can be resolved by well-known methods andthe optically active α-hydroxy ketal thus obtained can then be used inthe subject process to ultimately afford the desired acid in opticallypure form.

Alternatively, a microbiological process such as that described in SHELLINTERNATIONALE RESEARCH MAATSCHAPPIJ B. V.'s European Patent Appln. No.86 200987.5, published under No. 0 205215 on Dec. 17, 1986, may beemployed. According to the European application, a pharmaceuticallyactive compound of the type ##STR2## or a pharmaceutically active saltor ester thereof, which most preferably is naproxen or ibuprofen butwhich may be flurbiprofen or various other NSAIDs, is prepared instereospecific form by subjecting a compound of the formula ##STR3## tothe action of an appropriate microorganism. The desired acid is obtainedhaving at least 70% by weight in the S-configuration. Preferably, amicroorganism is selected such that the acid which is formed is at least90% by weight in the S-configuration. Use of this method has affordednaproxen with enantiomeric distributions of 98.9% S and 1.1% R in oneinstance, and distributions of 99.5% S and 0.5% R in another. Processesof this type may be utilized to prepare S(+) flurbiprofen for use in thepresent invention if the S(+) isomer can be obtained in sufficientpurity [ideally, at least 90% by weight S(+) isomer.]

When S(+) flurbiprofen is to be employed in the form of apharmaceutically acceptable, analgesically active simple metal saltthereof, such salt may be conveniently prepared by direct salificationof S(+) flurbiprofen by known methods. See, for example, deVincentiis,U.S. Pat. No. 4,440,787, which describes salts of(2',4'-difluoro-4-biphenyl)oxypropionic acid with metallic ions, such assodium, potassium, magnesium and calcium. Nonetheless, the free acidform is preferred. Compare also Armitage et al, U.S. Pat. No. 4,501,727,issued Feb. 26, 1985, which describes the N-methyl-D-glucamine salt offlurbiprofen. Such a salt may not only be used in oral or rectalcompositions, but, because it is highly soluble in water, it may be usedin the preparation of aqueous solutions of S(+) flurbiprofen salt forparenteral injection, as indicated by Armitage et al.

From the foregoing description, one of ordinary skill in the art caneasily ascertain the essential characteristics of the instant invention,and without departing from the spirit and scope thereof, can makevarious changes and/or modifications of the invention to adapt it tovarious usages and conditions. As such, these changes and/ormodifications are properly, equitably and intended to be within the fullrange of equivalence of the following claims.

We claim:
 1. The method of eliciting a sustained, enhanced antipyreticresponse in a human mammal suffering from elevated body temperature andin need of such treatment, comprising administering to such organism aunit dosage sustainedly enhancing, antipyretically effective amount ofthe S(+) flurbiprofen enantiomer, and said enantiomer beingsubstantially free of its R(-) flurbiprofen antipode.
 2. A methodaccording to claim 1, wherein the weight ratio of S(+) flurbiprofen toR(-) flurbiprofen is greater than 9:1.
 3. A method according to claim 2,wherein the weight ratio of S(+) flurbiprofen to R(-) flurbiprofen isgreater than or approximately equal to 20:1.
 4. A method according toclaim 3, wherein the weight ratio of S(+) flurbiprofen to R(-)flurbiprofen is greater than 97:3.
 5. A method according to claim 4,wherein the weight ratio of S(+) flurbiprofen to R(-) flurbiprofen isapproximately equal to or greater than 98:2.
 6. A method according toclaim 1, comprising administering to such organism from about 12.5 toabout 75 mg S(+) flurbiprofen.
 7. A method according to claim 1,comprising administering to such organism from about 12.5 to about 50 mgS(+) flurbiprofen.
 8. A method according to claim 1, comprisingadministering to such organism from about 12.5 to about 25 mg S(+)flurbiprofen.
 9. A method according to claim 2, comprising administeringto such organism from about 12.5 to about 75 mg S(+) flurbiprofen.
 10. Amethod according to claim 2, comprising administering to such organismfrom about 12.5 to about 50 mg S(+) flurbiprofen.
 11. A method accordingto claim 2, comprising administering to such organism from about 12.5 toabout 25 mg S(+) flurbiprofen.
 12. A method according to claim 3,comprising administering to such organism from about 12.5 to about 75 mgS(+) flurbiprofen.
 13. A method according to claim 3, comprisingadministering to such organism from about 12.5 to about 50 mg S(+)flurbiprofen.
 14. A method according to claim 3, comprisingadministering to such organism from about 12.5 to about 25 mg S(+)flurbiprofen.
 15. A method according to claim 4, comprisingadministering to such organism from about 12.5 to about 75 mg S(+)flurbiprofen.
 16. A method according to claim 4, comprisingadministering to such organism from about 12.5 to about 50 mg S(+)flurbiprofen.
 17. A method according to claim 4, comprisingadministering to such organism from about 12.5 to about 25 mg S(+)flurbiprofen.
 18. A method according to claim 5, comprisingadministering to such organism from about 12.5 to about 75 mg S(+)flurbiprofen.
 19. A method according to claim 5, comprisingadministering to such organism from about 12.5 to about 50 mg S(+)flurbiprofen.
 20. A method according to claim 5, comprisingadministering to such organism from about 12.5 to about 25 mg S(+)flurbiprofen.
 21. A method according to claim 1, wherein such organismis suffering from elevated body temperature associated with a cold orflu.
 22. A method according to claim 1, wherein the S(+) flurbiprofen isorally administered to such organism.
 23. A method according to claim 1,wherein the S(+) flurbiprofen is rectally administered to such organism.24. A method according to claim 1, wherein the S(+) flurbiprofen istopically administered to such organism.